What is Chronic Lymphocytic Leukemia (CLL)?

Chronic lymphocytic leukemia is a type of blood cancer that develops when the bone marrow produces too many lymphocytes. These important white blood cells help the body’s immune system fight off harmful invaders, such as viruses, bacteria and cancer. Lymphocytes are found in the blood and lymphatic tissues throughout the body, helping to defend against infections and disease.

CLL closely resembles acute lymphocytic leukemia (ALL), but the two conditions differ in terms of the maturity of the affected cells and how quickly the cancer develops. In CLL, the affected lymphocytes are mature and resemble healthy white blood cells. The abnormal cells grow and accumulate slowly, often over several years. Due to the gradual progression of CLL, immediate treatment is not always necessary. However, the cancer can potentially spread to the lymph nodes, liver or spleen before it is detected, so careful monitoring and a personalized treatment plan are essential. Chronic lymphocytic leukemia most commonly affects older adults.

By contrast, ALL is an aggressive, fast-growing leukemia that arises from immature white blood cells (lymphoblasts). Symptoms can develop quickly, requiring a prompt diagnosis and treatment. While acute lymphocytic leukemia can occur at any age, it is most often diagnosed in children.

What are the causes and risk factors for chronic lymphocytic leukemia?

While the precise cause of CLL is unknown, scientists have determined that the cancer results from changes that take place at a cellular level. More specifically, healthy lymphocytes undergo harmful mutations that cause the cells to grow uncontrollably, live longer than they should and build up in the bone marrow. The leukemia cells may then enter the bloodstream, travel throughout the body and spread to various organs and tissues.

Unlike many other cancers, chronic lymphocytic leukemia has not been conclusively linked to lifestyle choices, such as poor nutrition and tobacco use, or any particular infections. The few known risk factors are:

• Age – Approximately 90% of cases are diagnosed after age 50.
• Family history – Individuals with a parent, sibling or child who was diagnosed with CLL are twice as likely to develop the condition themselves.
• Exposure to certain chemicals – Studies have connected CLL to radon in the home, certain pesticides used in farming and Agent Orange, an herbicide used during the Vietnam War.

Is chronic lymphocytic leukemia preventable?

CLL is not considered preventable because its exact cause is not fully understood. Researchers have determined that the cancer results from genetic changes in the DNA of lymphocytes. In most cases, these mutations happen randomly. For this reason, there are no proven strategies—such as consuming a nutritious diet, exercising regularly and avoiding harmful substances—that can reliably prevent chronic lymphocytic leukemia.

That said, maintaining a healthy lifestyle—such as avoiding tobacco use, minimizing exposure to toxic chemicals and having regular medical checkups—can support overall health and help detect potential issues early.

What are the signs and symptoms of chronic lymphocytic leukemia?

Early-stage CLL may not cause noticeable symptoms. In many cases, the condition is diagnosed after a high lymphocyte count is detected in a blood test performed for an unrelated reason.

What are the early warning signs of chronic lymphocytic leukemia?

The initial warning signs of CLL are often vague and mild, such as:

• Unusual tiredness
• Unexplained weight loss
• Fever, chills and night sweats
• Swollen or enlarged lymph nodes
• Abdominal pain or fullness (caused by liver or spleen enlargement)

What are the most common symptoms of chronic lymphocytic leukemia?

As CLL progresses, leukemia cells may begin to crowd out healthy red blood cells, white blood cells and platelets. As these blood cells are depleted, additional symptoms may develop, such as:

• Overwhelming fatigue, muscle weakness and shortness of breath caused by a low red blood cell count (anemia)
• Recurrent infections due to a shortage of healthy white blood cells (leukopenia)
• Excessive bruising and bleeding resulting from a low platelet count

Most often people with CLL do not exhibit any symptoms and many diagnoses are discovered during blood work for another unrelated health issue. Typically, that’s when patients and physicians discover a high lymphocyte count.

Dr. Javier Pinilla

Malignant Hematology Department

What are the symptoms of advanced chronic lymphocytic leukemia?

As abnormal lymphocytes accumulate in the blood, bone marrow and organs, they may begin to interfere with the body’s ability to produce healthy blood cells and maintain normal immune function. Signs of advanced CLL can include:

• Severe fatigue or weakness that limits daily activities
• Frequent or prolonged infections, such as pneumonia and sinusitis
• Significant, unintentional weight loss over a short period
• Persistent fever and night sweats without an obvious infection
• Enlarged lymph nodes, liver or spleen that may cause noticeable swelling or discomfort in the neck, underarms, abdomen or groin
• Pain or fullness in the upper left abdomen due to spleen enlargement
• Bone or joint pain caused by marrow overcrowding
• Bleeding gums, frequent nosebleeds and easy bruising resulting from low platelet counts

As the cancer advances, the symptoms often intensify, and complications such as anemia and immune system disorders may develop.

What are the signs that chronic lymphocytic leukemia has spread?

CLL primarily affects the blood and bone marrow, but as it progresses, it can spread to other parts of the body. Possible signs include:

• Swelling in multiple lymph node regions, such as the neck, chest, abdomen and groin
• Enlargement of internal organs, particularly the spleen or liver, leading to abdominal pain or fullness
• Changes in blood cell counts, including a drop in red blood cells or platelets due to bone marrow involvement
• Unexplained fever, weight loss or drenching night sweats
• Bone pain or tenderness, indicating cancer cell buildup in the bone marrow
• Neurological symptoms, such as headaches, confusion or nerve pain, in rare cases where leukemia cells affect the brain or spinal cord

If chronic lymphocytic leukemia spreads to other organs or tissues, it can disrupt normal bodily functions and lead to more complex health challenges. Regular monitoring and follow-up with a hematologist are essential to detect CLL progression early and adjust the treatment plan as needed.

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How is chronic lymphocytic leukemia diagnosed?

CLL is typically diagnosed through a combination of physical examination, lab work, specialized procedures and imaging studies. These diagnostic tests can help the physician confirm the presence of leukemia cells and assess how advanced the cancer may be.

During a clinical evaluation, the physician will check for common indicators of cancer spread, such as lymph node swelling, spleen enlargement and liver tenderness. Because chronic lymphocytic leukemia often develops slowly and may not cause noticeable symptoms in its early stages, the condition is frequently detected incidentally during a routine blood test performed for an unrelated health concern.

What laboratory tests are used to diagnose chronic lymphocytic leukemia?

Several blood and genetic tests may be used to detect and confirm CLL. These include:

• Complete blood count (CBC) – This blood test measures the levels of red blood cells, white blood cells and platelets. In CLL, the white blood cell count—particularly lymphocytes—is usually elevated.
• Peripheral blood smear – A small sample of blood is microscopically examined by a pathologist, who can identify the abnormal or immature lymphocytes characteristic of CLL.
• Flow cytometry (immunophenotyping) – This laboratory technique analyzes the specific proteins (antigens) found on the surface of blood cells, which can help the physician identify leukemia cells and distinguish CLL from other types of leukemia and lymphoma.
• Genetic testing – Molecular and cytogenetic tests, including fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS), can detect genetic abnormalities, such as deletions and mutations in certain chromosomes (e.g., 13q deletion, 17p deletion and TP53 mutation). These findings can help the physician predict the behavior of the cancer and refine the treatment plan.

What procedures are used to diagnose chronic lymphocytic leukemia?

In addition to laboratory testing, certain procedures can help the physician confirm the diagnosis and assess the extent of the cancer. These include:

• Bone marrow aspiration and biopsy – The physician will remove a small sample of bone marrow, usually from the hip bone, for microscopic examination by a pathologist. The pathologist can confirm the presence of leukemia cells and determine the extent of marrow involvement.
• Lymph node biopsy – If enlarged lymph nodes are present and the diagnosis remains uncertain, the physician may remove all or a portion of an affected lymph node for microscopic examination by a pathologist.

What imaging tests are used to diagnose chronic lymphocytic leukemia?

While CLL is primarily diagnosed through blood and bone marrow testing, imaging may be used to help the physician assess how far the cancer has progressed and whether it has affected any internal organs. Common imaging tests include:

• Computed tomography (CT) scans – CT scans may reveal enlargement of the liver, spleen or lymph nodes that may not be noticeable during a physical examination.
• Ultrasound – This imaging test uses sound waves to create real-time pictures or video of soft tissues inside the body, which can help the physician evaluate the size of the spleen and liver and monitor for changes over time.
• Positron emission tomography (PET) scans – Though not always necessary for diagnosing CLL, a PET scan can help the physician identify areas of high metabolic activity within the body, such as tumor sites, or the transformation of CLL to a more aggressive form of lymphoma (Richter’s transformation).

How is chronic lymphocytic leukemia treated?

CLL treatment can vary based on several factors, including the stage of the cancer, the severity of the symptoms and the patient’s overall health. Because chronic lymphocytic leukemia often progresses slowly, some patients may not need treatment right away. Instead, they can be carefully monitored through periodic medical checkups and lab tests.

When CLL treatment is recommended, the physician will develop a personalized care plan aimed at controlling the progression of the cancer, managing the symptoms and enhancing the patient’s quality of life. Options may include chemotherapy, targeted therapy, immunotherapy, bone marrow transplantation (BMT) and/or radiation therapy.

How is chemotherapy used to treat chronic lymphocytic leukemia?

Chemotherapy uses powerful medications that target and destroy rapidly dividing cells throughout the body, including leukemia cells. Depending on the specifics of the treatment plan, the medications may be given orally or through intravenous (IV) infusion. Common chemotherapy drugs for CLL include fludarabine, cyclophosphamide and bendamustine.

Chemotherapy for chronic lymphocytic leukemia is often used alongside other treatments, such as monoclonal antibodies, for enhanced effectiveness. However, due to its potential side effects, such as fatigue, infection and nausea, chemo is being used less frequently as newer, targeted therapies for CLL have become more effective and better tolerated.

How is targeted therapy used to treat chronic lymphocytic leukemia?

Targeted therapy focuses on the specific molecules or pathways that leukemia cells rely on to grow and survive. These specialized medications are usually taken orally and tend to have fewer side effects than traditional chemotherapy.

Common targeted therapies for CLL include:

• BTK inhibitors, such as ibrutinib, acalabrutinib and zanubrutinib, which can block the signals that help leukemia cells grow
• BCL-2 inhibitors, such as venetoclax, which can trigger the death of leukemia cells by interfering with the proteins that prevent cell death (apoptosis)
• PI3K inhibitors, such as idelalisib and duvelisib, which can disrupt the signaling pathways essential to cancer cell survival

Targeted therapies have emerged as a cornerstone of CLL treatment, offering effective cancer control with manageable side effects while improving the long-term outcome for many patients.

How is immunotherapy used to treat chronic lymphocytic leukemia?

Instead of targeting the cancer directly, immunotherapy aims to amplify the power of the body’s own immune system, enhancing its ability to identify and destroy leukemia cells. The most common form of immunotherapy for CLL is monoclonal antibody treatment, which uses lab-made antibodies, such as rituximab, obinutuzumab and alemtuzumab. These specialized medications are designed to attach to specific proteins (CD20 or CD52) found on the surface of CLL cells, marking those cells for destruction by the immune system.

Another type of immunotherapy for chronic lymphocytic leukemia is chimeric antigen receptor (CAR) T-cell therapy, which involves genetically engineering the patient’s own T-cells in a lab to better recognize and attack the leukemia cells. While CAR T-cell therapy can potentially achieve a long remission in a patient with relapsed or refractory CLL, it may cause neurotoxicity and cytokine release syndrome (CRS), where inflammatory molecules (cytokines) are released and cause flu-like symptoms. However, these complications can usually be managed successfully.

How is bone marrow transplantation used to treat chronic lymphocytic leukemia?

BMT is an intensive procedure that may be considered for a patient with aggressive or treatment-resistant CLL. The goal is to replace the damaged or dysfunctional bone marrow with healthy blood-forming cells capable of regenerating normal blood and immune function.

Two main types of bone marrow transplantation may be used for treating chronic lymphocytic leukemia:

• Allogeneic stem cell transplant – This procedure uses blood-forming cells from a compatible donor, often a sibling or an unrelated individual with a matching tissue type. In addition to replenishing healthy cells, the donor’s immune cells can help destroy any remaining leukemia cells through the graft-versus-leukemia effect.
• Autologous stem cell transplant – In this approach, the patient’s own blood-forming cells will be collected before the patient receives high-dose chemotherapy to destroy as many leukemia cells as possible. The stored cells will then be reinfused into the patient to help restore normal bone marrow function.

Because bone marrow transplantation carries significant risks—including infection, graft-versus-host disease (GVHD) and other serious complications—it is typically reserved for younger, healthier patients and those whose leukemia has not responded to standard therapies. While not a first-line treatment, BMT can offer a potentially curative option for select individuals with advanced or high-risk CLL who have had limited success with other treatments.

How is radiation therapy used to treat chronic lymphocytic leukemia?

Radiation therapy uses focused, high-energy X-rays or other powerful beams to destroy cancer cells in a specific area of the body. Because CLL affects the blood and lymphatic system, radiation treatment is generally used to relieve symptoms rather than to cure the cancer. For example, it may be used in select cases to:

• Shrink enlarged lymph nodes that are causing pain or compressing nearby organs
• Reduce the size of an enlarged spleen that is creating discomfort
• Control localized leukemia symptoms that have not responded to other treatments

How is surgery used to treat chronic lymphocytic leukemia?

Surgery is rarely used as a primary treatment for CLL, mainly because the cancer does not produce solid tumors that can be surgically removed. However, in certain cases, a surgical procedure may be considered to manage complications associated with CLL. Possible surgical options include:

• Spleen removal (splenectomy) – If the spleen becomes significantly enlarged (splenomegaly) and causes pain, discomfort or a decrease in blood cell counts, the physician may recommend removing it. A splenectomy can help relieve symptoms and improve blood cell production.
• Lymph node biopsy – This procedure may be performed to help the physician confirm a CLL diagnosis or determine whether the cancer has transformed into a more aggressive type of lymphoma, such as Richter’s syndrome.

What are the possible complications of chronic lymphocytic leukemia?

Possible complications of CLL include:

• Anemia and bleeding problems – Leukemia cells may begin to crowd out healthy blood cells, potentially leading to anemia, easy bruising, excessive bleeding and overwhelming fatigue.
• Autoimmune conditions – CLL can cause the immune system to mistakenly attack the body’s own healthy cells. When red blood cells are destroyed, it can result in autoimmune hemolytic anemia; when platelets are targeted, it can lead to immune thrombocytopenia.
• Recurrent infections – Chronic lymphocytic leukemia weakens the immune system, making the body more susceptible to frequent and severe infections.
• Spleen and lymph node enlargement – CLL can cause significant and uncomfortable swelling of the spleen and lymph nodes.
• Progression to aggressive cancer – In rare cases, chronic lymphocytic leukemia can transform into a more serious form of lymphoma (Richter’s transformation).
• Secondary cancers – CLL may increase the risk of developing other blood-related cancers and skin cancers.

Managing these complications is often an important aspect of CLL treatment and care.

Benefit from world-class care at Moffitt Cancer Center

The multispecialty team in the Malignant Hematology Program at Moffitt has the specialized expertise necessary to effectively treat all types of leukemia and other cancers of the blood and bone marrow. If you would like to learn more about chronic lymphocytic leukemia, you can request an appointment with a specialist at Moffitt by calling 1-888-663-3488 or completing our new patient registration form online. We do not require referrals.